DESCRIPTION: (Verbatim from the Applicant's Abstract) The first generation of neuroimaging studies showed that anatomic pathology is present at the first episode (FE) of schizophrenia but left major unanswered questions about the initial pathology and its longitudinal course. Answers are critically needed to distinguish reflecting static encephalopathy from those that progress with the illness. Most knowledge comes from cross-sectional studies of chronic patients, but evidence suggests that pathology is less severe in FE patients, and that there may be illness-associated deterioration. It is now suspected also that some antipsychotic drugs (APDs) affect brain structure. These findings highlight the need to study first episode patients, enabling accurate identification of pathology that cannot reflect treatment or long-term illness effects. The findings further point to the need for longitudinal follow-up of sufficient duration that anatomic changes and related functional changes can be expected to occur. New research must also include adequate control over treatments and assessments of nutritional status to help distinguish initial and ongoing illness-related pathologies from factors unrelated to the illness. To enable relevance to current practice, changes in brain structure and structure-function relations must be evaluated in patients receiving novel APDs as first-line treatments. The proposed research uses magnetic resonance imaging (MRI) methods in a unique sample of antipsychotic-na&iuml;ve, first-episode patients (N=116), and demographically matched healthy volunteers (N=84), who are participating in a study now supported by the NIMH. Patients will be randomized to first-line treatment with one of three new APDs (olanzapine, risperidone, or ziprasidone), and followed intensively for 3 years with a broad range of clinical, neurocognitive, and functional outcome assessments. MRI exams with multiple acquisition sequences will be conducted before treatment, after 16 weeks of controlled treatment, and after 3 years. Both established and innovative approaches to morphometric analysis will be used, enabling detailed mapping of neuroanatomic variations that are associated with group differences, longitudinal changes, and functional indices. The data obtained will have major implications for segregating initial from ongoing anatomic pathology and specifying the relations of initial and ongoing pathologic processes to multidimensional response patterns and long-term outcomes.